Enteroviruses are small, non-enveloped RNA viruses responsible for poliomyelitis, encephalitis, acute heart failure or severe hepatitis in newborns, and other life threatening infections. In the United States recent outbreaks of coxsackievirus B1 (CVB1) infections and coxsackievirus A6 served as reminders of the ongoing threat raised by these pathogens. Similarly, outbreaks of enterovirus 71 have occurred nearly annually in Europe and the Asia-Pacific region for almost 20 years, and could potentially lead to epidemics in North America if imported. We have recently identified a novel group of closely related small molecules that inhibit the replication of coxsackievirus B (CVB) variants, polioviruses, and other enteroviruses. We propose a two-year study to identify derivatives of this group of compounds with robust antiviral activity against pathogenic enteroviruses. Successful completion of these goals could ultimately lead to the development of antiviral drugs useful in cases of life-threatening enterovirus infections and that could potentially play a role in the eradication of poliovirus circulation.